ACDC/Adiponectin Polymorphisms Are Associated With Severe Childhood and Adult Obesity

Abstract

Common single nucleotide polymorphisms (SNPs) in the ACDC adiponectin encoding gene have been associated with insulin resistance and type 2 diabetes in several populations. Here, we investigate the role of SNPs ؊11,377C>G, ؊11,391G>A, ؉45T>G, and ؉276G>T in 2,579 French Caucasians (1,229 morbidly obese and 1,350 control subjects). We found an association between severe forms of obesity and ؊11,377C (odds ratio 1.23, P ‫؍‬ 0.001) and ؉276T (1.19, P ‫؍‬ 0.006). Surprisingly, alternative alleles ؊11,377G and ؉276G have been previously reported as risk factors for type 2 diabetes. Transmission disequilibrium tests showed a trend in overtransmission (56.7%) of a risk haplotype 1 (C) -1 (G) -1 (T) -2 (T) including ؊11,377C and ؉276T in 634 obesity trios (P ‫؍‬ 0.097). Family-based analysis in 400 trios from the general population indicated association between obesity haplotype and higher adiponectin levels, suggesting a role of hyperadiponectinemia in weight gain. However, experiments studying the putative roles of SNPs ؊11,377C>G and ؉276G>T on ACDC functionality were not conclusive. In contrast, promoter SNP ؊11,391G>A was associated with higher adiponectin levels in obese children (P ‫؍‬ 0.005) and in children from the general population (0.00007). In vitro transcriptional assays showed that ؊11,391A may increase ACDC activity. In summary, our study suggests that variations at the ACDC/adiponectin gene are associated with risk of severe forms of obesity. However, the mechanisms underlying these possible associations are not fully understood. Diabetes 55: [545][546][547][548][549][550] 2006 A diponectin is a potent insulin-sensitizing adipokine that acts on several peripheral tissues. In contrast to leptin, plasma adiponectin is reduced in obese children (1) and adults (2), and low adiponectin levels correlate with increased risk for type 2 diabetes (2). However, hypoadiponectinemia associates more with insulin resistance than with the degree of obesity (3). Associations between the adiponectin encoding gene (ACDC) variants and insulin resistance, type 2 diabetes, and/or cardiovascular diseases were reported in several but not all studies (4,5). The strongest associations are seen in two promoter single nucleotide polymorphisms (SNPs) Ϫ11,377CϾG and Ϫ11,391GϾA, the exon 2 synonymous SNP ϩ45TϾG, and the intronic SNP ϩ276GϾT. Alleles showing higher risk for type 2 diabetes associated with decreased adiponectin levels (6,7). Associations between ACDC SNPs and BMI have been previously described (8), but their contribution to risk for severe forms of obesity is not known. Here, we report genetic evidence for the role of ACDC SNPs in the risk for childhood and morbid adult obesity. We also provide functional data supporting the role for promoter SNP Ϫ11,391GϾA in the modulation of adiponectinemia. RESEARCH DESIGN AND METHODSWe genotyped 424 nuclear families including 634 obese children (defined as BMI Ͼ97th percentile for age and sex). Ninety-five unrelated obese children recruited in Toulouse were also genotyped (onli...

Promoter adiponectin polymorphisms and waist/hip ratio variation in a prospective French adults study

“…4,[25][26][27] Decreased adiponectin levels were described in weight-stable obese subjects. However, many studies have reported an association between obesity risk and hyperadiponectinemia associated with polymorphisms, 9,18,28 which were in accordance with our results. The physiological mechanisms to explain these results are a complex question to address.…”

“…According to previous studies 9, 18,19 we found standardized linkage disequilibrium between À11391 and À11377 SNPs. In this context, haplotype combinations could clarify associations involving these correlated markers.…”

“…Furthermore, transcriptional activity of the ADIPOQ promoter, measured with a luciferase assay, demonstrated that the À11391G4A polymorphism had a 2.5-fold increase in transcriptional activity, which was in accordance with higher adiponectin levels observed in À11391A carriers. 18 In the same order of idea, our results show positive correlation between adiponectin levels and weight gain. Thus, a high level of adiponectin concentration is predictive to weight gain over the years.…”

“…Despite the low number of subjects measured for adiponectin levels, our results were in close agreement with other studies. [8][9][10]18,19 It has been previously described in different obese and nonobese populations that plasma concentrations of adiponectin are significantly higher in À11391A allele carriers, while À11377C4G ADIPOQ polymorphism induced lower adiponectin levels. Furthermore, transcriptional activity of the ADIPOQ promoter, measured with a luciferase assay, demonstrated that the À11391G4A polymorphism had a 2.5-fold increase in transcriptional activity, which was in accordance with higher adiponectin levels observed in À11391A carriers.…”

“…The physiological mechanisms to explain these results are a complex question to address. Bouatia-Naji et al 18 suggested the physiological contribution of adiponectin to weight gain over time may be mediated by its insulin-sensitizing action in adipose tissue. Indeed, Fu et al 29 suggested a new role for adiponectin as a factor augmenting programmed gene expression responsible for adipogenesis (that is, PPARg) and increasing lipid content and insulin responsiveness of the glucose transport system in adipocytes.…”